This invention relates to novel fatty acid analog substrates of myristoylating enzymes and, more particularly, to oxy- and thio-substituted fatty acid analogs which are useful in the fatty acid acylation of peptides and proteins.
Fatty acid acylation of specific eukaryotic proteins is a well established process which can conveniently be divided into two categories. On the one hand, palmitate (C.sub.16) is linked to membrane proteins via ester or thioester linkage post-translationally, probably in the Golgi apparatus.
On the other hand, it is known that myristate (C.sub.14) becomes covalently bound to soluble and membrane proteins via amide linkage early in the protein biosynthetic pathway. In the N-myristoylated proteins, amino-terminal glycine residues are known to be the site of acylation.
A variety of viral and cellular proteins have been shown to be thus modified by the covalent attachment of myristate linked through an amide bound to glycine at their amino termini. An example of a most thoroughly studied myristoylated protein is the transforming protein of Rous sarcoma virus, p60.sup.v-src.
The myristoylation reaction can be represented as follows: ##STR1##
Further background information on the above protein fatty acid acylation can be had by reference to the following series of articles by scientists associated with the Washington University School of Medicine:
Towler and Glaser, Biochemistry 25, 878-84 (1986); PA1 Towler and Glaser, Proc. Natl. Acad. Sci. USA 83, 2812-2816 (1986); PA1 Gly-Asn-Ala-Ala-Ala-Ala-Arg-Arg and PA1 Gly-Asn-Ala-Ala-Ser-Tyr-Arg-Arg. PA1 A. 11-(Ethylthio)undecanoic acid CH.sub.3 CH.sub.2 S(CH.sub.2).sub.10 COOH PA1 B. 11-(Ethoxy)undecanoic acid CH.sub.3 CH.sub.2 O(CH.sub.2).sub.10 COOH PA1 C. 5-(Octylthio)pentanoic acid CH.sub.3 (CH.sub.2).sub.7 S(CH.sub.2).sub.4 COOH PA1 D. 11-(Methoxy)undecanoic acid CH.sub.3 O(CH.sub.2).sub.10 COOH PA1 E. 12-(Methoxy)dodecanoic acid CH.sub.3 O(CH.sub.2).sub.11 COOH PA1 F. 5-(octyloxy)pentanoic acid CH.sub.3 (CH.sub.2).sub.7 O(CH.sub.2).sub.4 COOH PA1 G. 10-(Propylthio)decanoic acid CH.sub.3 (CH).sub.2 S(CH.sub.2).sub.9 COOH PA1 H. 10-(Propoxy)decanoic acid CH.sub.3 (CH.sub.2).sub.2 O(CH.sub.2).sub.9 COOH PA1 I. 11-(1-Butoxy)undecanoic acid CH.sub.3 (CH.sub.2).sub.3 O(CH.sub.2).sub.10 COOH PA1 J. 10-(2-Propynoxy)decanoic acid HC.tbd.CCH.sub.2 O(CH.sub.2).sub.9 COOH
Towler et al., Proc. Natl. Acad. Sci. USA 84, 2708-2712 (1987);
Towler et al., J. Biol. Chem. 262, 1030-1036 (1987); and
Towler et al., Ann. Rev. Biochem. In Press (1988).
Unique synthetic peptides having relatively short amino acid sequences which are useful as substrates of myristoylating enzymes are described in U.S. Pat. No. 4,740,588. Examples of such peptides are